title: Signal-dependent fra-2 regulation in skeletal muscle reserve and satellite cells.
abstract: Activator protein-1 (AP-1) is a ubiquitous transcription factor that paradoxically also has some tissue-specific functions. In skeletal muscle cells, we document that the AP-1 subunit, Fra-2, is expressed in the resident stem cells (Pax7-positive satellite cells) and also in the analogous undifferentiated 'reserve' cell population in myogenic cultures, but not in differentiated myofiber nuclei. Silencing of Fra-2 expression enhances the expression of differentiation markers such as muscle creatine kinase and myosin heavy chain, indicating a possible role of Fra-2 in undifferentiated myogenic progenitor cells. We observed that Fra-2 is a target of cytokine-mediated extracellular signal-regulated kinase-1/2 signaling in cultured muscle cells, and extensive mass spectrometry and mutational analysis identified S320 and T322 as regulators of Fra-2 protein stability. Interestingly, Fra-2 S320 phosphorylation occurs transiently in activated satellite cells and is extinguished in myogenin-positive differentiating cells. Thus, cytokine-mediated Fra-2 expression and stabilization is linked to regulation of myogenic progenitor cells having implications for the molecular regulation of adult muscle stem cells and skeletal muscle regeneration.
authors.affiliation: Department of Biology, York University, 4700 Keele Street, Toronto, Ontario, Canada.
authors.forename: N S
authors.initials: NS
authors.lastname: Alli
authors.forename: E C
authors.initials: EC
authors.lastname: Yang
authors.forename: T
authors.initials: T
authors.lastname: Miyake
authors.forename: A
authors.initials: A
authors.lastname: Aziz
authors.forename: H
authors.initials: H
authors.lastname: Collins-Hooper
authors.forename: K
authors.initials: K
authors.lastname: Patel
authors.forename: J C
authors.initials: JC
authors.lastname: McDermott
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D016207:Cytokines / Q000502:physiology; D051921:Fos-Related Antigen-2 / Q000737:chemistry / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology*
chemical_list: D016207:Cytokines; D051921:Fos-Related Antigen-2; C497873:Fosl2 protein, mouse; C092073:cardiotrophin 1